Methoxy cephalosporin intermediate

A methoxy head, cephalosporin technology, applied in bulk chemical production, organic chemistry and other directions, can solve the problems of low reactivity, complex reaction, long deprotection route and so on

Inactive Publication Date: 2008-07-02
北京金源化学集团有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The above various synthetic methods have good practical application value for the synthesis of methoxycephalosporins, but due to the characteristics of the structure of 7-ACA itself, that is, C 4 bit, C 7 bits need to be protected during the reaction while C 3 The reactivity of the position is relatively low, which leads to the synthesis from 7-ACA to methoxycephalosporins. In terms of nature, it needs to be greatly improved

Method used

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  • Methoxy cephalosporin intermediate
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 7-Phenylacetamido-3-vinyl-4-cephemic acid p-methoxybenzyl ester

[0024]Add 10 g of p-methoxybenzyl 7-phenylacetamido-3-chloromethyl-4-cephemate, 3 g of NaI, 5.93 g of triphenylphosphine, and 60 mL of acetone into a five-neck flask, and stir at 20°C for 1 h. Then 60 mL of dichloromethane and 17 mL of 37% formaldehyde aqueous solution were added, and the temperature was lowered to 15°C. Keeping this temperature, 20 mL of 1 mol / L sodium hydroxide solution was added dropwise. Continue stirring for 30 min after dropping, pour the mixture into 60 mL of 0.1 mol / L hydrochloric acid, stir for 10 min, and separate the organic phase. The aqueous phase was extracted with 60 mL of dichloromethane. The organic phases were combined and washed with 100 mL of water. Concentrate the organic phase under reduced pressure at 25°C, evaporate part of the solvent, add 150 mL of methanol preheated to 30°C, add seed crystals, and crystallize after 30 minutes. Concentration was continued, pa...

Embodiment 2

[0026] 7-Phenoxyacetylamino-3-pyridylmethyl-4-cephalosporanic acid benzhydryl ester

[0027] Dissolve 10 g of 7-phenoxyacetamido-3-iodomethyl-4-cephalosporanic acid diphenylmethyl ester in 80 mL of dichloromethane, adjust the temperature to 8-10 °C, add 4 mL of pyridine dropwise, complete the addition in 10 minutes, and raise the temperature to React at 20-25°C for 2 hours, after the reaction is complete, lower the temperature to 0-5°C, add 100mL of isopropyl ether, stir for 1h, filter with suction, wash the filter cake with 20mL of isopropyl ether, drain it, and dry it in vacuum at room temperature for 6h to obtain a light yellow powder 7-Phenoxyacetylamino-3-pyridylmethyl-4-cephalosporanic acid diphenylmethyl ester, the yield is 90%.

Embodiment 3

[0029] 7-Naphthylacetamido-7α-methoxy-3-(1-methyl-1,3,4,5-tetrazolium)thiomethyl-4-cephenoic acid p-nitrobenzyl ester

[0030] Add 50mL of treated anhydrous methanol to a 250mL three-neck flask, protect it with nitrogen, cool it to below -80 degrees with liquid nitrogen, add 1.0g lithium methoxide, and add 5.9g 7-naphthylacetamido-3-(1-methyl -1,3,4,5-tetrazolium)thiomethyl-4-cephemic acid p-nitrobenzyl ester was dissolved in 50mL of anhydrous tetrahydrofuran, and added dropwise to the reaction system at a relatively fast speed, while ensuring that the system temperature was at -80 below the degree. After 5 minutes, 1.5 mL of tert-butyl hypochlorite was added. Stir at -80°C for 30 minutes. Trimethyl phosphite and glacial acetic acid were then added. The temperature was raised to room temperature, the solvent was evaporated, dissolved in dichloromethane, washed successively with saturated sodium chloride, sodium bicarbonate and saturated sodium chloride. After drying over a...

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Abstract

The invention relates to a synthesis method of an intermediate of methoxyl cephalosporin. C3 site methyl halide of a cephems compound with C4,7 site being protected, instead of the ordinary 7-ACA, is used as a material, functionalized at C3 site, and then methoxylated at C7 site, finally de-protected, and the intermediate of methoxyl cephalosporin is prepared. The compound can be conveniently used in the synthesis of various methoxyl cephalosporin medicines. The invention has apparent advantages of clear synthesis route, less steps, less and inexpensive reagents, comparatively single solvent, convenience for recovery and recycling, low material cost and operation expenses.

Description

[0001] technical field [0002] The present invention relates to β-lactams, in particular to the preparation of intermediates for synthesizing cephalosporins. Background technique [0003] Methoxycephalosporin refers to a kind of Cephamycin C (Cephamycin C) produced by the fermentation of Streptomyces lactamdurans through semi-synthesis. 7 A cephalosporin with a trans-methoxy group. The presence of methoxy prevents the approach of the lactam ring and the enzyme molecule, enhances the stability of the drug against β-lactamase, and improves the activity against anaerobic bacteria, making this class of antibiotics more resistant to β-lactamase It has strong antibacterial effect on some bacteria producing β-lactamase. The antibacterial performance of methoxycephalosporins is similar to that of cephalosporins. According to the classification method of cephalosporins, cefmetazole and cefoxitin belong to the second generation, while cefotetan and cefminox belong to the third genera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/16
CPCY02P20/55
Inventor 张喜军陈朝晖邱明建张雅丽张春山
Owner 北京金源化学集团有限公司
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